P-042: POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS ANALYSIS OF HYDROXYUREA, IN ADULT PATIENTS WITH SICKLE CELL DISEASE (SCD) RECEIVING BOTH TABLETS OR CAPSULES FORMULATIONS, AND EVALUATION OF DISEASE MARKERS
Authors: BARTOLUCCI P., LEZZAR S., HABIBI A., DE LUNA G., JEBALI A., MARTINO S., NOIZAT C., FAUROUX C., GALACTÉROS F.
Journal: HemaSphere (2022)

Purpose: Hydroxycarbamide (HU) is used sickle-cell disease (SCD) after having showed to induce fetal haemoglobin (HbF)[1]. Although this was an old molecule, few pharmacokinetics-pharmacodynamics (PK/PD) models were developed on HU. 1.Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008; 358 (13): 1362-69. 10.1056/NEJMct0708272. Materials and methods: The aim of this analysis was to develop retrospectively, a population PK (popPK) and PK/PD models to patients receiving both HU formulations (capsules or tablets), in order to: Describe the exposure-efficacy relationships between HU and biomarkers (HbF% and mean corpuscular volume (MCV)) Compare PK/PD parameters, HbF% and MCV, obtained with the results observed in Paule et al[1], Simulate HbF% and MCV levels according to two regimens (7/7 vs 5/7 days) for 14 weeks at 1000 mg daily dose. We combine three PK datasets from renal study[1], bioequivalence study[2] and retrospective PKPD data from patients followed in hospital Mondor. A popPK model for HU was established. The selected popPK model was used in PK/PD modelling, consisting of two independent PK/PD models respectively for HbF% and MCV. Indirect PK/PD models were tested for both relations since drug impact on each marker was observed after few weeks of treatment. 1.Clinical study report, “Evaluation of the impact of renal function on the pharmacokinetics of hydroxyurea (siklos®) in normal-renal, hyperfiltrating and renal failure sickle cell disease patients (DARH)”. Final version, 02-February-2018. 2.Clinical study report, “a phase I pharmacokinetics study of hydroxyurea 1,000 mg coated breakable tablets and hydroxyurea 500 mg capsules in paediatric, adolescent and adult patient treated for sickle cell syndrome”. Final version, 15 april 2005. 1.Paule I, Sassi H, Habibi A, Pham KP, Bachir D, Galactéros F, Girard P, Hulin A, Tod M. Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen. Orphanet Journal of Rare Diseases. 2011. Results: The popPK model was confirmed as a linear model with a 2-compartment parameterized in terms of CL/F, V2/F, Q/F, V3/F and ka, allometric scale with exponents of 0.75 and 1 for clearances and volumes of distribution, respectively was integrated. For a bodyweight of 70 kg, clearance was 12.1 L/h with a variability of 63.9%, V2/F and V3/F were respectively 48.1 and 31.1 L. Population parameters were very closed to observed CL/F and V/F obtained in the study published by Paule et al2. Conclusion: Precision of the model was acceptable and individual prediction of HbF% levels were good (Figure 1). For MCV, HU is assumed to reduce kout (inhibition of the elimination of the response) (Figure 2). Regarding simulations, MCV reached a plateau around 3 months of HU and HbF% continue to increase over 14 weeks (Figure 3). Indeed, the increase of HbF% and MCV levels was more marked than using the regimen with 2 days of HU interruption (especially in patients having the highest values). The daily regimen seemed to be more appropriate regarding both responses. Both HbF% and MCV are good biomarkers for evaluation of SCD.Figure 1. pcVPC of level of HbF% vs. time after treatment initiation (left: lin-lin scale; right: lin-log scale) Figure 2. pcVPC of level of MCV vs. time after treatment initiation (left: lin-lin scale; right: lin-log scale)Figure 3. SIMULATED HBF% AND MCV LEVELS USING PKPD MODEL, CONSIDERING 2 DOSING REGIMENS (left: HBF%; right: MCV) The authors do not declare any conflict of interest